ABSTRACT ? Project 1 There is a critical need to protect adolescents and young adults from HIV infection through the development of an early life vaccine strategy that elicits protective immunity prior to sexual debut. However, to date, efforts to develop a vaccine that can elicit protective broadly neutralizing antibodies (bnAbs) have been challenged both by limited engagement of bnAb epitopes by germline B cell receptors and levels of somatic hypermutation needed for achievement of bnAb, as well as the likely need for long term boosting and several years time to evolve the B cell responses towards broad neutralization. Two recent findings suggest that the low risk of HIV acquisition in the period between breastfeeding and sexual debut might provide unique window and immune landscape for vaccine-induced bnAb production: 1) the high capacity of the pediatric immune system over that of adults for the development of bnAb responses during HIV infection, and 2) the remarkably low somatic hypermutation level in bnAbs isolated from HIV-infected children, which may provide the opportunity to direct development of bnAb B cell clones through vaccination. Yet, there is a gap in our understanding of the potential advantages of the early life immune system over that of adults for induction of bnAbs via vaccination. Thus, Project 1 proposes to compare immune response to long-term immunization with the bnAb germline- targeting native-like HIV Env trimer: BG505 GT1.1 SOSIP trimer immunogen initiated in infancy compared to that of pre-adolescents (as well as comparison to BG505 Env mRNA infant vaccination in Project 2). Specifically, Aim 1 of this project will test the hypothesis that the unique flexibility of the early life immune system and differential B cell tolerance mechanisms will allow enhanced engagement and evolution of B cell clones through bnAb germline-targeting SOSIP immunization compared to that in older monkeys. Aim 2 will test the hypothesis that the initiation of HIV B cell lineage vaccination in early life compared to preadolescence will result in antibody maturation that will translate into enhanced protective vaccine efficacy against HIV acquisition prior to sexual debut. Finally, Aim 3 will test the hypothesis that early life immunologic and microbiologic signatures predict the development of HIV-neutralizing responses to SOSIP vaccination by working with the Program's Integrated Systems Immunology Core, to assess the transcriptomic and microbiome signatures that associated with the induction of bnAb precursor and tier 2 virus neutralization responses. Furthermore, to establish translatability, we will compare the overall kinetics of vaccine-elicited somatic hypermutation in U.S and Malawian infants to that of infant monkeys. Taken together, the results of this Project will provide critical information about age-specific vaccine-elicited immune responses relevant to refining HIV Env vaccine strategies that take advantage of immune development, such as target population, vaccine schedule, novel adjuvants, and long term boosting that will be needed to achieve a high level of bnAb induction in human populations.